Abstract: Krabbe disease (KD) is a rare hereditary condition with no cure currently available. KD is due to the deficiency of a lysosomal enzyme called galactosyl-ceramidase (GALC), which causes the accumulation of a cytotoxic sphingolipid, psychosine (PSY). The early-infantile and most widespread form of this lysosomal storage disorder (LSD) is degenerative, rapidly progressive and lethal.
As the name suggests, LSDs are characterized by the accumulation of undigested material. The main physiological tool own by the cell to get rid of waste material and to recycle cellular components is autophagy. However, while there is plenty of literature describing impaired autophagy features in most of LSDs, little is known about autophagy in KD. Hence, we tried to fill this gap investigating autophagy in the twitcher mouse, which is the most common animal model for KD. In particular, we studied some of the basic autophagy markers, such as LC3 and p62. Our data suggested an autophagic dysregulation.
However, this information may be a blessing in disguise and autophagy could prove to be a double-edged sword. As a matter of fact, the idea that LSDs should be regarded as disorders of autophagy is becoming established and, interestingly, there is a vast number of autophagic modulators which can be tested as potential therapies. Autophagy, in fact, is physiologically finely regulated and modulators operate on different levels of the autophagic pathway. However, for the time being, we focused on lithium, an FDA-approved drug that has been used for decades as a mood-stabilizer in the treatment of bipolar disorder. In a recent publication, we increased autophagy by lithium administration in a KD cellular model and obtained an improvement in cell viability in presence of PSY. At present, we are testing lithium in vivo, administering it in drinking water.